YY1 plays an essential role at all stages of B-cell differentiation
YY1 plays an essential role at all stages of B-cell differentiation
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DOI：
10.1073/pnas.1606297113
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发表时间：
2016-07-05
影响因子：
11.1
通讯作者：
Feeney, Ann J.
中科院分区：
文献类型：
--
作者：
Kleiman, Eden;Jia, Haiqun;Feeney, Ann J.
Ying Yang 1（YY 1）是一种广泛表达的转录因子，对前B细胞发育至关重要。然而，YY1在其他B细胞群中的作用从未被研究过。最近的生物信息学分析数据表明YY 1参与了生发中心（GC）B细胞转录程序。与这一预测雅阁，我们证明了C.1Cre缺失YY 1完全阻止了GC B细胞和浆细胞的分化。为了确定YY 1是否也是其他B细胞群分化所需的，我们用CD 19-Cre缺失YY 1，发现所有外周B细胞亚群，包括B1 B细胞，都需要YY 1来分化。过渡期1（T1）B细胞对YY 1的依赖性最强，即使是对YY 1的一半剂量也敏感，并且对他莫昔芬诱导的Cre的短期YY 1缺失也敏感。我们发现YY 1发挥其作用，部分是通过促进B细胞的存活和增殖。ChIP测序显示，YY1主要结合启动子，结合YY1的基因的途径分析显示富集核糖体功能、线粒体功能（如生物能量学）和与转录相关的功能（如mRNA剪接）。通过差异表达基因的RNA测序分析，我们证明YY 1通常激活线粒体生物能量学相关基因，而通常下调转录、mRNA剪接、NF-κ B信号通路、AP-1转录因子网络、染色质重塑、细胞因子信号通路、细胞粘附和细胞增殖相关基因。我们的研究结果表明，YY1在调节整个B细胞分化的所有阶段的广泛的一般过程中发挥着至关重要的作用。
Ying Yang 1 (YY1) is a ubiquitously expressed transcription factor shown to be essential for pro-B-cell development. However, the role of YY1 in other B-cell populations has never been investigated. Recent bioinformatics analysis data have implicated YY1 in the germinal center (GC) B-cell transcriptional program. In accord with this prediction, we demonstrated that deletion of YY1 by C.1Cre completely prevented differentiation of GC B cells and plasma cells. To determine if YY1 was also required for the differentiation of other B-cell populations, we deleted YY1 with CD19-Cre and found that all peripheral B-cell subsets, including B1 B cells, require YY1 for their differentiation. Transitional 1 (T1) B cells were the most dependent upon YY1, being sensitive to even a half-dosage of YY1 and also to short-term YY1 deletion by tamoxifen-induced Cre. We show that YY1 exerts its effects, in part, by promoting B-cell survival and proliferation. ChIP-sequencing shows that YY1 predominantly binds to promoters, and pathway analysis of the genes that bind YY1 show enrichment in ribosomal functions, mitochondrial functions such as bioenergetics, and functions related to transcription such as mRNA splicing. By RNA-sequencing analysis of differentially expressed genes, we demonstrated that YY1 normally activates genes involved in mitochondrial bioenergetics, whereas it normally down-regulates genes involved in transcription, mRNA splicing, NF-kappa B signaling pathways, the AP-1 transcription factor network, chromatin remodeling, cytokine signaling pathways, cell adhesion, and cell proliferation. Our results show the crucial role that YY1 plays in regulating broad general processes throughout all stages of B-cell differentiation.